The overall goal of this proposal is to identify means for improving ?-cell regeneration in the adult pancreas. With previous BCBC funding we have developed a transgenic model of inducible total or partial ?-cell ablation (RIP-DTR). In these mice, ?-cell regeneration occurs after near total ?-cell loss, and this relies on the transdifferentiation of adult mature ?-cells to ?-cells. In this proposal we will test, among different aspects, i) whether ?-cell regeneration in RIP-DTR mice can be enhanced by promoting the observed spontaneous ?-to-?-cell conversion. ?-cell regeneration occurs by ?-cell replication in other diabetes models of less severe ?-cell ablation. Regeneration in RIP-DTR mice is less efficient than in these mouse models probably because DT treatment leaves almost no ?-cells (DT stands for diphtheria toxin, the agent used to induce ?-cell ablation in these mice). Accordingly, ?-cell repopulation principally occurs in RIP-DTR mice by a mechanism of ?-cell reprogramming. One of our objectives will be ii) to determine if age plays a role in ?-cell regeneration / ?-cell reprogramming , since proliferation in islets has been shown to profoundly decline in older rodents and humans. In addition, we will examine the molecular mechanisms controlling ?- to ?-cell transdifferentiation in RIP-DTR mice. These analyses will be performed in parallel with studies aimed at iii) exploring whether cell fate reprogramming is a common feature of different adult pancreatic cell types, and is not restricted to ? - cells only. The heterologous origin of new ?-cells is particularly interesting, since the almost complete ?-cell depletion achieved in RIP-DTR mice recreates a condition very similar to the situation found in Type 1 diabetic patients. PUBLIC HEALTH RELEVANCE: Understanding the mechanisms of ?-cell regeneration and identifying the cells and factor(s) that enhance the formation and/or growth and/or survival of ?-cells should have a high impact on the development of new treatments for human T1D.